Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis

Objective Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor alpha (TNF alpha) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFa inhibitors. Methods TNF alpha-naive patients with RA, who had available DNA and initiated TNF alpha inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response. Results After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n = 142), etanercept (n = 12), and adalimumab (n = 42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor beta, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response. Conclusion In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNF alpha inhibitors. A GSEA suggested that the transforming growth factor beta, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response. Pharmacogenetics and Genomics 22: 577-589 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.